N-substituted n-arylsulfonyl ureas for producing a hypoglycaemic effect

ABSTRACT

N-arylsulfonyl-1,2,4,5-tetrahydro-3H-3-benzazopine-3carboxamides and addition salts thereof with bases, which compounds have useful hypoglycaemic action, as well as starting materials for their production; therapeutic compositions containing these carboxamides or their pharmaceutically acceptable addition salts and processes of producing hypoglycaemic effects in mammals. An illustrative embodiment is N-(p-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3carboxamide.

United States Patent [151 3,689,649

Dietrich 1 Sept. 5, 1972 [54] N-SUBSTITUTED N-ARYLSULFONYL [56] RetenneaCited UREAS FOR PRODUCING A HYPOGLYCAEMIC EFFECT Wm STATES Inventor:Hem-l m I sonncnweg AF 3,239,503 3/1966 Korgev et al. ..260I239.6

leshelm swmfland Primary Examiner-Jerome D. Goldberg [221 Filed; July16, 1970 Attorney-Karl F. Jorda and Marlin J. Spellman [2]] App]. No.:62,757 [57] ABSTRACT Related US. Application DataN-arylsulfonyl-l,2,4,5-tetrahydro-3H-3-benzazopine- 3-carboxamides andaddition salts thereof with bases, [62] DIVlSlOlI of Ser. No. 667,363,Sept. 13, I967, which compounds have useful hypoglycaemic action 3575926as well as starting materials for their production;

therapeutic compositions containing these carbona- [52] US. Cl..424/229, 424/244 mides or their pharmauuficany acceptabk addition IIILClsalts and of p oducing cf. [58] Field of Search ..424/229, 244 feelsin mammals, An illustrative embodiment is N-(ptolylsulfonyD-l,2,4,5-tetrahydro-3H-S-benzazepine-S- carboxamide.

ZSCIIIIImNODI'aWings N-SUBSTITUTED N-ARYLSULFONYL UREAS FOR PRODUCING AHYPOGLYCAEMIC EFFECT CROSS-REFERENCE TO A RELATED APPLICATION DETAILEDDISCLOSURE,

The invention relates to N'-substituted N-arylsulfonyl ureas havingvaluable pharmacological properties. More particularly the inventionpertains to N-arylsulfonyl-l,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamides and to additionsalts thereof with inorganic or organic bases. The invention is furtherconcerned with processes for the production of these carboxamides andthese addition salts and also comprehends tetrahydro-3H-3-benzazepinederivatives which are used as starting materials in said processes. Itis further an object of the invention to provide therapeuticcompositions consisting essentially of l a N-arylsulfonyI-l,2,4,5-tetrahydro-3H-3- benzazepine-Ii-carboxamide according to theinvention, or a pharmaceutically acceptable addition salt thereof withan inorganic or organic base, and

2. a pharmaceutical carrier. Another object of the invention is toprovide processes of producing hypoglycaemic effects in mammalsinvolving the administration to said mammals of an effective amount ofan inventive N-arylsulfonyl-l,2,4,5-tetrahydro-3I-l-3-benzazepine-3-carboxamide, or a pharmaceutically acceptable additionsalt thereof with an inorganic or organic base.

Compounds of the formula wherein R, represents hydrogen, halogen up tothe atomic number 35, a lower alkyl, lower alkoxy, lower alkylthio,lower alkanoyl or amino group, R, represents hydrogen, or R,R,represents the tetramethylene group, and their addition salts withinorganic or organic bases, have not been known up to now.

In the compounds of formula I,R, may be in the o-, mor p-position andmay be exemplified for lower alkyl as e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec. butyl, tert. butyl, n-penty],isopentyl or 2,2-dimethyl-propyl; for lower alkoxy as e.g. methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy, tert.butoxy, n-pentoxy, isopentoxy as well as 2,2-dimethylpropoxy; for loweralkylthio as e.g. methylthio, ethylthio, n-propylthio, isopropylthio,nbutylthio, isobutylthio, sec. butylthio, tert. butylthio, npentylthio,isopentylthio as well as 2,2-dimethylpropylthio and, for lower alkanoyl,as e.g. acetyl, propionyl, Z-methyl-propionyl, butyryl, 2-methyl-butyrylas well as 3-methyI-butyryl.

The compounds of the above formula are produced according to theinvention by reacting an isocyanate derivative of the formula IItrimethylene or, the

wherein R, represents hydrogen, halogen up to the atomic number 35, theamino group or a lower alkyl, lower allcoxy, lower alkythio or loweralkanoyl group, or it represents a group which can be converted into anamino group by hydrolysis, reduction or reductive cleavage,

R, represents hydrogen or R,R represents the trimethylene ortetramethylene group, or a reactive functional derivative of a carbamicacid of the formula III I: OH

R,', R, or R,'R have the meanings given in formula I or II, withl,2,4,5-tetrahydro-3H-S-benzazepine [cf. P. RUGGLI et al., Helv. Chim.Acta 18, 1388 (1935) or with an alkali metal derivative of thiscompound, the reaction being performed, if desired, in the presence of acondensing agent and, preferably, in an inert solvent, if necessaryhydrolyzing or reducing the reaction product obtained to convert thegroup R, into the free amino group and, if desired, converting thereaction product obtained into a salt with an inorganic or organic base.

As reactive functional derivatives of carbamic acids of the formula III,e.g. their halides, particularly the chlorides, and their lower alkylesters, particularly the methyl or ethyl esters, also the phenyl estersare used. Also, amides, nitroamides, lower alkylamides, di (lower)alkylamides, diphenylamides, particularly N- methylamides,N,N-dimethylamides, in addition N- acylamides such as benzoylarnides,and 2-oxo derivatives of polymethyleneimides such as the2-oxo-den'vative of pyrrolidinides, piperidides, hexamethyleneimides oroctamethyleneimides are suitable.

As example of such functional derivatives of carbamic acids of theformula III can be mentioned: N-phenylsulfonyl carbamic acid chloride,methyl-, ethylor phenyl N-phenylsulfonyl carbamates, N-phenylsulfonylurea, N-nitro-N-phenylsulfonyl urea, N-methyl-N'- phenylsulfonyl urea,N,N-dimethyl-N'-phenylsulfonyl urea, N,N-diphenyl-N'-phenylsulfonylurea, N- benzoyl-N'-phenylsulfonyl urea, N-phenylsulfonyl-Z-oxo-pyrrolidinel-carboxamide, N-phenylsulfonyl-Z- oxo-piperidinel-carboxamide, N-phenyl-sulfonyl-Z- oxo-hexahydrol H-azepinel-carboxamide and N- phenylsulfonyl-Z-oxo-octahydrol I-l-azeninel-carboxamide, or derivatives of those compounds the groups R, or R,'R ofwhich at the benzene nucleus conform with the groups explicitly listedfor R, or R,R at the end of formula I.

The reaction is performed, e.g. in the cold or by heating in an inertorganic solvent. Suitable inert organic solvents are, e.g. hydrocarbonssuch as benzene, toluene or xylene, ether-type liquids such as diethylether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such asmethylene chloride and lower ketones such as acetone or methylethylketone.

The reaction of an isocyanate, carbarnic acid ester or urea can beperformed in the absence of solvents or diluents. In general, nocondensing agent is necessary; if desired, however, an alkali alcoholatecan be used as R (III) such agent. Other condensing agents which can beused in the reaction of an isocyanate are tertiary organic bases;isocyanates, however, can also be used in the form of an additionproduct with a tertiary organic base.

The reaction of a carbarnic acid halide with l,2,4,5-tetrahydro-3H-3-benzazepine is preferably performed according to theinvention in the presence of an acid binding agent. As such, inorganicbases or salts are used such as an alkali hydroxide, acetate, hydrogencarbonate, carbonate and phosphate, e.g. sodium hydroxide, sodiumacetate, sodium hydrogen carbonate, sodium carbonate and sodiumphosphate or the corresponding potassium compounds. In addition, calciumoxide, calcium carbonate as well as calcium phosphate and magnesiumcarbonate can also be used. lnstead of inorganic bases or salts, alsoorganic bases are suitable, e.g. pyridine, trimethylamine ortriethylamine, N,N di-isopropylamine, triethylamine or collidine. Usedin excess, these can also serve as solvents. For the reaction accordingto the invention with a carbarnic acid chloride, instead ofl,2,4,5-tetrahydro- 3H-3-benzazepine, an alkali metal derivative of thisbase such as a sodium, potassium, or lithium derivative can be used.

The conversion of a group R, of the reaction product into the free aminogroup which converts such product into a compound of formula l isperformed by hydrolysis, reduction or reductive cleavage depending onthe type of the group R,'.

Groups R, which can be converted into the free amino group by hydrolysisare, e.g. acylarnino, particularly lower alkanoyl-amino, groups such asthe acetamido group or lower alkoxy or phenoxy carbonylamino groups suchas the ethoxycarbonylamino or phenoxycarbonylamino group. Other examplesare substituted methyleneamino groups such as the benzylideneamino orp-dimethylarnino-benzylidenearnino group. The hydrolysis to liberate theamino group can be performed, e. g. in acid medium such as by heating indilute methanolic hydrochloric acid, or, when R, is a lower alkoxy orphenoxy carbonylamino group, also under mild alkaline conditions, e.g.with IN to 2N sodium hydroxide solution, at room temperature.

An example of a group R, which can be converted by reduction into theamino group is the nitro group and examples of such groups which, byreductive cleavage, lead to the amino group are the phenylazo orp-dimethylamino-phenylazo groups. ln general, these groups can bereduced catalytically, e.g. with hydrogen in the presence of Raneynickel, palladium or platinum charcoal, in an inert solvent such asethanol. In addition, other usual reduction processes can also be used,e.g. the reduction of nitro groups or the reductive cleavage of awegroups with the aid of iron in acetic or hydrochloric acid.

Compounds of the formula I are produced by a second process according tothe invention by reacting a reactive functional derivative oftetrahydro-3H-3- benzazepine-Ii-carboxylic acid with a sulfonamide ofthe formula IV wherein R,', R, and R,R have the meanings given informulas l or ll or reacting such tetrahydro-3H-3-benzazepine-3-carboxylic acid derivative with an alkali metal derivativeof a compound of formula IV, if necessary hydrolyzing or reducing thereaction product obtained to convert the group R, into the free aminogroup and, if desired, converting the reaction product obtained into asalt with an inorganic or organic base.

The halides, particularly the chloride, are used as reactive functionalderivatives of tetrahydro-3l-l-3- benzazepine-ll-carboxylic acid.Suitable alkali metal derivatives of sulfonamides of formula IV are,e.g. sodium, potassium or lithium derivatives.

The reaction of the halides according to the invention is preferablyperformed in an inert solvent in the presence of an acid binding agent.Suitable inert organic solvents are, e.g. hydrocarbons such as benzene,toluene or xylene, ethereal liquids such as diethyl ether, dioxane ortetrahydrofuran, chlorinated hydrocarbons such as methylene chloride andlower ketones such as acetone or methylethyl ketone. Inorganic bases orsalts are used as acid binding agents, e.g. an alkali hydroxide,acetate, hydrogen carbonate, carbonate and phosphate, such as sodiumhydroxide, sodium acetate, sodium hydrogen carbonate, sodium carbonateand sodium phosphate or the corresponding potassium compounds. Alsocalcium oxide, calcium carbonate and calcium phosphate and magnesiumcarbonate can be used. lnstead of inorganic bases or salts, also organicbases are suitable, e.g. pyridine, trimethylamine or triethylamine,N,N-di-isopropylamine, triethylamine or collidine. Used in excess, thesecan also be used as solvents.

The subsequent conversion of a group R, in the reaction product into thefree amino group, which converts the reaction product into a compound offormula I is performed by hydrolysis, reduction or reductive cleavage asdescribed above depending on the type of the group RTetrahydro-3l-l-3-benzazepine-3-carbonyl chloride is an example of areactive functional derivative oftetrahydro-3I-l-3-benzazepine-3-carboxylic acid which can be used asstarting material. This starting compound which is obtained, e.g. whentetrahydro-3H-3- benzazepine is reacted with phosgene in benzene, is newand forms part of the invention.

Compounds of formula l are produced by a third process according to theinvention by desulfurizing a thiourea derivative of the formula Vwherein R,', R, or R 'R, have the meanings given in formulas or ll, ifnecessary, hydrolyzing or reducing the reaction product obtained toconvert the group K, into the free amino group and, if desired,converting the reaction product obtained into a salt with an inorganicor organic base.

The desulfurization can be performed, e.g. with an oxidizing agent inacid, alkaline or neutral medium. Suitable oxidizing agents are, e.g.potassium ferricyanide, iron-llI-chloride, potassium permanganate,potassium chlorate, potassium hypochlorite or potassium hypoioditesolution. Hydrogen peroxide or sodium peroxide in alkaline solution,e.g. sodium hydroxide solution, are particularly advantageous oxidizingagents. In addition, heavy metal compounds such as mercury oxide or leadoxide can also be used for the desulfurization. These metal oxides areadvantageously used in an aqueous organic solvent. Suitable organicsolvents are, e. g., lower alkanols such as methanol, alkane polyolssuch as glycol or glycerine, ethereal liquids such as tetrahydrofuran ordioxan, ketones such as acetone or methylethyl ketone, carboxylic acidamides such as N,N-dimethylformamide and, also, urea derivatives such asl, l ,3,3-tetramethyl-urea.

The subsequent conversion of a group R, in the reaction product into thefree amino group which converts the product into a compound of formula Ican be performed as described at the end of the first process. Thehydrolysis of group R, to the amino group there mentioned, however, canalso be performed simultaneously with the desulfurization.

Starting materials of the formula V are, e.g., those compounds thesubstituents R, and R of which confonn to the groups listed at the endof fonnulas I or II for R,, R or R,R or R,', R,, or R,R., respectively.These starting materials are new and form part of the invention. Anexample of such a starting material is N- (p-tolylsulfonyl )-l ,2,4,5-tetrahydro- 3H-3- benzazepine-3-thiocarboxamide which can beproduced, e.g., from p-tolylsulfonyl isothiocyanate andtetrahydro-3H-3-benzazepine in toluene. Other starting materials of thistype can be produced analogously.

Compounds of the formula I according to the invention are produced by afourth process by hydrolyzing a compound of the formula VI s OQNZUAN I)wherein R, ',R or R,'R have the meanings given in formulas or ll and Xrepresents a halogen atom or a lower alkoxy or lower alkythio group, ifnecessary reducing or further hydrolyzing the reaction product obtainedto convert the group R, into the free amino group and, if desired,converting the reaction product obtained into a salt with an inorganicor organic base.

X as a halogen atom preferably represents the chlorine atom, as loweralkoxy or lower alkythio group it represents, e.g., the methoxy, ethoxyor the methylthio or ethylthio group.

When X is a halogen atom, the hydrolysis is ad vantageously performedwith the aid of an inorganic base, e.g., with sodium hydroxide, and whenX is a lower alkoxy or lower alkylthio group, instead of the inorganicbase, a halogen hydracid, e.g., hydrochloric acid is used. The reactionis advantageously performed in an organic solvent which is miscible withwater. Such solvents are, e.g., ketones such as acetone or methylethylketone, ether type liquids such as dioxane or tetrahydrofuran and alsocarboxylic acid amides such as N,N-dimethyl formamide. The subsequentconversion of a group R, in the reaction product into the free aminogroup can be performed as described at the end of the first process. Ifthe substituent R, can be converted into the amino group by hydrolysisthen this hydrolysis can be performed simultaneously to the reactionaccording to the invention.

Starting materials of formula VI are, e.g., those compounds thesubstituents R, and R of which conform to the groups listed followingformulas l or ll for R,, R or R,R,, or R,', R,, or R, 'R,, respectively.Such a group of starting materials are, e.g.,N-phenylsulfonyltetrahydro-BH-3-benzazepine-3-carboximidoyl chloridessubstituted in the benzine ring by R, and R These are obtained, e.g.,from phosgene and correspondingly substitutedN-phenylsulfonyl-tetrahydro- 3H-3-benzazepine-3-thiocarboxamides, whichare starting materials for the third process. The reaction can beperformed, e.g., in tetrahydrofuran. The reaction products can beconverted into another group of starting materials of the formula V]wherein the substituent X is a lower alkythio group if they are reacted,e.g., with the sodium salt of a lower alkane thiol such as methanethiol. This second group of starting materials areN-phenylsulfonyl-tetrahydro-3H-3-benzazepine-3- thiocarboximido acidlower alkyl esters, e.g.,N-phenylsulfonyl-tetrahydro-3H-3-benzazepine-3-thiocarboximido acidmethyl esters which are substituted in the benzene nuclei by the groupsR, and R Corresponding N-phenylsulfonyl-tetrahydro-3H-3-benzazepine-3-carboximido acid lower alkyl esters compounds of formula V] wherein X isa lower alkoxy group are obtained, e.g., by using a sodium salt of alower alkanol as reaction component in the reaction instead of a sodiumsalt of a lower alkane thiol.

The same starting materials can also be produced starting fromtetrahydro-3l-l-3-benzazepine. This is converted with, e.g., cyanogenbromide, into tetrahydro-3l-I-3-benzazepine-3-carbonitrile which isconverted in a solution of hydrochloric acid in a lower alkanol into a2-lower alkyl-3-(tetrahydro-3H-3- benzazepin-3-yl )-pseudo urea. Thispseudo urea can be condensed, e.g., with a benzene sulfochloridesubstituted by the groups R, and R while splitting off hydrogenchloride.

The above described starting materials of formula VI are new and form apart of the invention.

As stated above, the invention also concerns the conversion of theN-arylsulfonyl-l,2,4,5-tetrahydro-3H-3- benzazepine-S-carboxamides intosalts with inorganic or organic bases. These salts have the samevaluable pharmacological properties as the free compounds of formula Iand can be prepared according to the usual methods well known in theart. lnorganic or organic bases such as alkali or alkaline earthhydroxides, carbonates or bicarbonates, triethanolamine, choline, N'-dimethylor N-(B-phenylethyl)- biguanide, can be used for example forsalt formation.

The N-aiylsulfonyll ,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide offormula I as well as their addition salts with inorganic or organicbases have now been found to unexpectedly exhibit valuablepharmacological properties. On oral or parenteral administration theyshow hypoglycaemic action which characterizes them as suitable for thetreatment of diabetes. Representative of these compounds areparticularly N-phenylsulfonyll ,2,4,5-tetrahydro-3H-3-benzazepine-S-carboxamide,

N-( p-tolylsulfonyl )-1 ,2,4,5 -tetrahydro-3H-3-benzazepine-3-carboxamide,

N-(p-chloro-phenylsulfonyl 1 ,2,4,5 -tetrahydro-3 H-3-benzaeepine-3-carboxamide,

7 N-(p-fluoro-phenylsulfonyl)- 1 ,2,4,5 -tetrahydro-3l-l- 3-benzazepine1 3-carboxamide, N-( p-methoxy-phenylsulfonyl )-l,2,4,5-tetrahydro- 3l-l-S-benzazepine-Zl-carboxamide,N-(p-ethoxy-phenylsulfonyl )-1 ,2,4,5-tetrahydro-3H-3-benzazepine3-carboxamide, N-(p-amino-phenylsulfonyl)-1,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxamide,N-(p-acetyl-phenylsulfonyl )-1 ,2,4,5 -tetrahydro-3H-3-benzazepine-3-carboxamide, N-(p-methylthio-phenylsulfonyl)-1,2,4,5-tetrahydro- 3H-3-benzazepine-3-carboxamide, N-(o-tolylsulfonyl 1,2,4,5-tetrahydro-3H-3- benzazepine-B-carboxamide, N-(m-chloro-phenylsulfonyl)-1 ,2,4,5-tetrahydro-3l-I-3-benzazepine-3-carboxamide, and N-(indan-S-yl-sulfonyl )-1 ,2,4,5-tetrahydro-3H-3- benzaaepine-3-carboxamide, as well as the additionsalts thereof with inorganic or organic bases. Particularly interestingcompounds according to the invention which exhibit hypoglycaemic actionto a favorable degree are N-arylsulfonyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamides of the formula wherein R has the meaningas given in formula 1 for R,, 30

as well as the addition salts thereof with inorganic or organic bases.

The hypoglycaemic action of the compounds according to the invention mayillustratively be demonstrated e. g. by means of the following test:

The substance to be tested for hypoglycaemic action is suspended in tapwater with the aid of tragacanth and is administered by means of astomach sound. Five rats of an average weight of 190 g which have notbeen fed for 6% hours before the start of the test, and/or six rabbitsof an average weight of 2.5 Kg which have not been fed for 24 hoursbefore the start of the test, are used as test animals.

Blood samples are taken from the tail vein of the animals when usingrats in the test, and from the ear vein of the animals when usingrabbits, immediately before, and, in intervals, up to 24 hours after,administration of the test substance. The blood sugar is determinedaccording to HAGEDORN-JENSEN, Biochemische Zeitschrift 135, 46 (1923),and, with the autoanalyzer, according to W. S. l-lofiman, J. Biol. Chem.120, 51 (1937), respectively.

N-(p-tolylsulfonyl 1 ,2 ,4,5-tetrahydro-3H-3- benzazepine-S-carboxamideadministered in this test in amounts of from 20 to 100 mg/kg ofbodyweight in the rabbit causes a significant, long lasting reduction ofthe blood sugar.

On administration of 100 mg/kg of bodyweight, N-(p-methylthio-phenylsulfonyl l ,2,4 ,5 -tetrahydro-3H-3-benzazepine-3-carboxamide shows in this test a significant reductionof the blood sugar in the rat.

The compounds of the invention have a favorable therapeutic index, theirtoxicity is low the LD, of e.g. N-( p-chloro-phenylsulfonyl )-1 ,2,4,5-tetrahydro-3l-l-3- benzazepine-3-carboxamide in the mouse is 2,400mg/kg p.o.

For their intended use the N-arylsulfonyl-l,2,4,5-tetrahydro-3l-l-S-benzazepine-ll-carboxamides of formula l as well astheir pharmaceutically acceptable addition salts with inorganic ororganic bases are administered, preferably, orally in amounts dependingon the species, age and weight of the subject under treatment; ingeneral the daily doses vary between about 100 mg and about 2,000 mg.

For administration purposes, preferably, the above mentioned therapeuticcompositions are used. These compositions are presented for e.g. oraladministration in dosage units such as tablets, dragees (sugar coatedtablets), and the like.

Dosage units such as dragees (sugar coated tablets), tablets, preferablycontain 100 500 mg of an active substance according to the invention,i.e. 20 percent of a compound of formula I. They are produced, e.g. bycombining the active substance with e.g. solid pulverulent carriers suchas lactose, saccharose, sorbitol, mannitol; starches such as potatostarch, maize starch or arnylopectin, also larninaria powder or citruspulp powder; cellulose derivatives of gelatine, optionally with theaddition of lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights, to form tablets ordragee cores. The latter are coated, e.g. with concentrated sugarsolutions which can also contain, e.g. gum arabic, talcum and/ortitanium dioxide, or with a laquer dissolved in easily volatile organicsolvents or mixture of solvents. Dyestuffs can be added to thesecoatings, e.g. to distinguish between varying dosages of activesubstance.

The following prescriptions further illustrate the production of tabletsand dragees:

a. 1000 g of N-(p-tolylsulfonyl)-l,2,4,5-tetrahydro-3H-3-benza2epine-3-carboxamide are mixed with 550 g of lactose and 292 gof potato starch, the mixture is moistened with an aqueous solution of8.0 g of gelatine and granulated through sieve. After drying, 60.0 g ofpotato starch, 60.0 g of talcum, 10.0 g magnesium stearate and 20.0 g ofcolloidal silicon dioxide are mixed in and the mixture is pressed into10,000 tablets each weighing 200 mg and containing mg of activesubstance. If desired, the tablets can be grooved for better adaptationof the dosage.

b. A granulate is prepared from 1000 g of N-(pmethylthio-phenylsulfonyl)-1 ,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide, 379 g of lactoseand the aqueous solution of 6.0 g of gelatine. After drying, thegranulate is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g oftalcum, 60.0 g of potato starch and 5.0 g of magnesium stearate and themixture is pressed into 10,000 dragee cores. These are then coated witha concentrated syrup made from 533.5 g of crystallized saccharose, 20.0g of shellac, 75.0 g of gum arabic, 250 g of talcum, 20 g of colloidalsilicon dioxide and 1.5 g

0 of dyestuff, and dried. The dragees obtained each weigh 240 mg andcontain 100 mg of active substance,

The following examples further illustrate the production of the newcompounds of formula 1 and of hitherto undescribed intermediateproducts, but they are by no means the only methods of producing same.The temperatures are given in degrees Centigrade. Percentages are givenby weight.

EXAMPLE 1 14.7 g of 1,2,4,S-tetrahydro-3l-l-3-benzazepine (cf. P. Ruggliet a1, Helv. Chim. Acta 18, 1388 (1935)) in 50 ml of anhydrous acetoneare added to 20 g of p-tolyl sulphonyl isocyanate in 150 ml of acetone.The crude product crystallizes out of the reaction solution. Thesolution is diluted with 200 ml of water, the crystals are filtered offunder suction and taken up in 2N ammonia. An insoluble residue isfiltered ofiand the clear solution is added dropwise to 2N hydrochloricacid while stirring and cooling. The crude N-(p-tolylsulphonyl)- 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide precipitates from thesolution. It is filtered off under suction, washed with water and driedin vacuo at 60 whereupon it melts at 158.5 160. The substancecrystallizes from a small amount of methanol and it decomposes at 101.The crystals contain methanol.

EXAMPLE 2 14.7 g of 1,2,4,5-tetrahydro-3l-l-3-benzazepine are added to18.3 g of phenylsulphonyl isocyanate in 100 ml of anhydrous toluene. Anexothermic reaction occurs on completion of which the precipitatedcrystals are filtered off under suction and washed with petroleum ether.The crystals are dissolved in 150 ml. of cold acetone and a smallresidue is removed from the solu' tion by filtration. The filtrate isconcentrated to half its volume and is diluted with water until itbegins to go opaque. The precipitated crystalline end product isfiltered off under suction, washed with water and dried in vacuo at 60.The N-phenylsulphonyl-l,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamideobtained melts at 176179.

EXAMPLE 3 Starting from 14.7 g of l,2,4,5-tetrahydro-3H-3- benzazepine,the following end products are obtained analogously to Example 2:

a. with 22 g of p-chlorophenylsulphonyl isocyanate, N-(p-chlorophenylsulphonyl 1 ,2,4 ,5 -tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. 166.5-168.

b. with 20.1 g of p-fluorophenylsulphonyl isocyanate, N-(p-fluorophenylsulphonyl 1 ,2,4,5-tetrahydro-3 H-3-benzazepine-Ii-carboxamide, M.P. l01103, and

c. with 28.4 g of p-nitrophenylsulphonyl isocyanate, the newintermediate N-(p-nitrophenylsulphonyl)- l,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. 203208. This ishydrogenated in 300 ml of methanol and 4 g of platinum charcoal at roomtemperature and under normal pressure to form N-(pamino-phenylsulphonyll ,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide.

EXAMPLE 4 24.3 g of ethyl N-(p-tolylsulphonyl)-carbamate and 14.7 g of1,2,4,5-tetrahydro-3H-3-benzazepine in 400 ml. of anhydrous dioxane areboiled for 3.5 hours. The solution is then concentrated under vacuum andthe residue is recrystallized from ethyl acetate. The N-(ptolysulphonyl)-1 ,2 ,4,5-tetrahydro-3l-l-3-benzazepine- 3-carboxamide obtained meltsat 158.5 160 and, according to its melting point and the melting pointwhen mixed with the compound obtained according to Example 1, it isidentical with that compound.

EXAMPLE 5 The following end products are obtained analogously to example4 starting from 14.7 g of 1,2,4,5-tetrahydro- 3H-3-benzazepine:

a. with 25.9 g of ethyl N-(p-methoxy-phenylsulphonyl)-carbamate, N-(p-methoxy-phenylsulphonyl)- 1,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamide, M.P. l50-152, and

b. with 27.3 g of ethyl N-(p-ethoxy-phenylsulphonyl )-carbamate, N-(p-ethoxy-phenylsulphonyl )-1 ,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. I7l-172.

EXAMPLE 6 14.7 g of l,2,4,5-tetrahydro 3H-3-benzazepine and 21.5 g ofsulphanilyl urea are refluxed in 1,000 ml of dioxane, ammonia beingdeveloped. After 1 hour, the reaction mixture is concentrated and 200 mlof water are added. The crystals obtained are dissolved in 2N ammonia.The filtered solution is acidified with 2N hydrochloric acid whilestirring and cooling. The pureN-(p-amino-phenylsulphonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide is filtered off under suction, washed withwater and dried in vacuo at 60. It melts at 182-l 83.

EXAMPLE 7 EXAMPLE 8 Starting from 14.7 g of l,2,4,5-tetrahydro-3H-3-benzazepine, the following end products are obtained analogously toexample 7:

a. with 24.4 g of (p-ethoxy-phenylsulphonyl)-urea, N-(p-ethoxy-phenylsulphonyl 1 ,2,4,5-tetrahydro-3 H-3-benzazepine-3-carboxamide. M.P. 17 ll 72. According to its meltingpoint and the melting point when mixed with the compound obtainedaccording to Example 5(b), it is identical with that compound;

b. with 24.2 g of (p-acetyl-phenylsulphonyl)-urea, N-(p-acetyl-phenylsulphonyl 1 ,2,4,5-tetrahydro-3I-l-3 benzazepine-3-carboxamide;

c. with 21.8 g of (p-fluorophenylsulphonyl)-urea, N-(p-fluoro-phenylsulphonyl 1 ,2,4,S-tetrahydro-3H-3-benzazepine-3-carboxamide. According to its melting point and themelting point when mixed with the compound obtained according to Example3(b), it is identical with that compound;

d. with 23.7 g of (m-chlorophenylsulphonyl)-urea, N-(m-chloro-phenylsulphonyl 1 ,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamide, M.P. I 34-1 37;

e. with 24.6 g of (p-methylthio-phenylsulphonyl)- urea,N-(p-methylthio-phenylsulphonyl)-1,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamide, M.P. -150;

f. with 24 g of (indan-S-ylsulphonyl)-urea, N-(indan- -ylhsulphonyl )-1,2 ,4,5-tetrahydro-3l-l-3-benzazepine- 3-carboxamide, and

g. with 21.4 g of (o-tolylsulphonyl)-urea, N-(o-tolylsulphonyl )-1 ,2,4,5 -tetrahydro-3H-3-benzazepine-3- carboxamide, M.P. 169-171.

EXAMPLE 9 15.3 g of 1,2,4,5-tetrahydro-3H-3-benzazepine and 25.6 g of1-acetyl-3-(p-tolylsulphonyU-urea are refluxed for 1 hour in 1,000 ml ofanhydrous dioxane while stirring vigorously. The reaction mixture isthen concentrated, water is added, the crystalline crude product isfiltered off under suction and washed with water. The crude product isrecrystallized from ethyl acetate whereupon pureN-(p-tolysulphonyl)-l,2,4,5- tetrahydro-3l-l-3-benzazepine-3-carboxamideis obtained. According to its melting point and the melting point whenmixed with the compound obtained according to example 1, it is identicalwith that compound.

EXAMPLE 10 Starting from 14.7 g of l,2,4,5-tetrahydro-3l-l-3-benzazepine, the following end products are obtained analogously toexample 9:

a. with 28.2 g of NJp-tolylsulphonyl)-2-oxo-pyrrolidine-l -carboxamide(M.P. l45-l47] or with 29.6 g of N-( p-tolylsulphonyl)-2-oxo-piperidine- 1 -carboxamide, (M.P. l06-l07),N-(p-tolylsulphonyl)-l,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxamide.According to its melting point and the melting point when mixed with thecompound obtained according to Example it is identical with thatcompound;

b. with 31.7 g of N-(p-chlorophenylsulphonyl)-2-oxo-piperidine-l-carboxamide (M.P. l38140) or with 35.9 g ofN-(p-chloro-phenylsulphonyll-2-oxo-octahydro- 1 l-l-azoninel-carboxamide, N-( p-chlorophenylsulphonyl )-l,2,4,5-tetrahydro-3H-3-benzazepine-3- carboxamide. According to itsmelting point and the melting point when mixed with the compoundobtained according to Example 3(a), it is identical with that compound,and

c. with 31.7 g of N-(p-chlorophenylsulphonyl)-2- oxo-hexahydro-ll-l-azepinel -carboxamide (M. P. 1

12] .5"), N-(p-chloro-phenylsulphonyl)-1 ,2,4,5-tetrahydro-3l-l-3-benzazepine-3-carboxamide, which is identical with thecompound obtained according to Example 10(b).

EXAMPLE 1 l a. 17.1 g of p-toluene sulphonamide are dissolved in 600 mlof dioxane and 5.6 g of pulverized potassium hydroxide are added. 2 l .0g of tetrahydro 3I-l-3- benzazepine-3-carbonyl chloride are addeddropwise to the clear, hot solution and the whole is refluxed for 10hours. The reaction mixture is then concentrated in vacuo and 150 ml of2N hydrochloric acid are added. The crystals obtained are dissolved indilute ammonia, a small amount of an undissolved substance is filteredoff and the filtrate is again acidified with dilute hydrochloric acid.The precipitated crystals are washed with water. After drying at 60under vacuum, the pureN-(p-tolylsulphonyl)-tetrahydro-3l-l-3-benzazepine-3- carboxamide meltsat l67.5-l69 and is identical with the compound obtained by examples 1or 4.

The starting material, tetrahydro-3H-3-benzazepine- 3-carbonyl chloride,is produced as follows:

b. 76,2g(0.5 mol) of tetrahydro-3l-l-3-benzazepine are dissolved in 200ml of anhydrous benzene and then, at room temperature, phosgene isintroduced while stirring. The temperature rises to 60 and thetetrahydro- 3I-l-3-benzazepine hydrochloride crystallizes out. Excessphosgene is removed in a stream of nitrogen. Thetetrahydro-3l-l-3-benzazepine hydrochloride (M.P. 214-2l5) is thenfiltered off and the residue is distilled. Thetetrahydro-3H-3-benzazepine-3-carbonyl chloride is used withoutpurification.

EXAMPLE 12 Starting from 21.0 g of tetrahydro-3H-3-benzazepine-3-carbonyl chloride, the following end products are obtainedanalogously to Example 1 l (a):

a. with 19.4 g of p-chlorobenzene sulphonamide, N-(p-chloro-phenylsulphonyl)-tetrahydro-3H-3- benzazlepine-3-carboxamide,M.P. 1 66 1 68;

b. with 23.6 g of p-bromobenzene sulphonamide, N-p-bromo-phenylsulphonyl )-tetrahydro- 3H-3 benzazepine-3-carboxamide,

c. with 20.1 g of p-ethoxybenzene sulphonamide, N-(p-ethoxy-phenylsulphonyl)-tetrahydro-3l-[-3- benzazepine-3-carboxamide,M.P. 171-172;

d. with 18.7 g of p-methoxybenzene sulphonamide,N-(p-methoxy-phenylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide, M.P. l50152.

e. with 19.7 g of S-indane sulphonamide, N-(indan-S-ylsulphonyl)-tetrahydro-3H-3-benzazepine-3-carboxamide, and

f. with 17.5 g of p-fluorobenzene sulphonamide, N-(p-fluorophenylsulphonyl)-tetrahydro-3H-3- benzazepineG-carboxamide,M.P. 101l03.

EXAMPLE 13 a. 36.1 g of N-(p-tolysulphonyl)-tetrahydro-3H-3-benzazepine-3-thiocarboxamide are dissolved in ml of 2N sodium hydroxidesolution and 50 ml of 30 percent hydrogen peroxide are added dropwisewhile stirring. The reaction mixture is refluxed for 3 hours. Then,after cooling, it is acidified with 2N hydrochloric acid. The crudeproduct precipitates; it is filtered off and recrystallized from ethylacetate whereupon N-(ptolylsulphonyl )-tetrahydro- 3 l-l-3-benzazepine-3-carboxarnide is obtained, M.P. l58-160.

b. the starting material, N-(p-tolylsulphonyl)-tetrahydro-3l-l-3-benzazepine-3-thiocarboxamide, is produced as follows:21.3 g of p-tolylsulphonyl isothiocyanate are added to 14.7 g oftetrahydro-3l-l-3- benzazepine in 50 ml of anhydrous toluene. Oncompletion of the strongly exothermic reaction, petroleum ether is addedto the reaction product until it begins to turn opaque whereupon thesubstance crystallizes. The pure N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-3-thiocarboxamide melts at 129- 130, solidifies andmelts at 210.

EXAMPLE 14 a. 36.3 g of N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-Ii-carboximidoyl chloride are dissolved in 200 ml ofdioxane, 200 ml of 2N sodium hydroxide are added and the whole is heatedfor 1 hour in a water bath. After cooling, the reaction mixture isacidified with 2N hydrochloric acid. The precipitated crystals arerecrystallized from ethyl acetate. The pure N-(ptolylsulphonyl )-tetrahydro-3H-3-benzazepine-3-carboxamide melts at l58-l 60.

The starting material, N-(p-tolylsulphonyU-tetrahydro-3H-3-benzazepine-3-carboximidoyl chloride, is produced asfollows:

b. Phosgene is introduced for hours into a solution of 36.1 g ofN-(p-tolylsulphonyl)-tetrahydro-3H-3- benzazepine-3-thiocarboxamide in500 ml of anhydrous tetrahydrofuran. The reaction is slightlyexothermic. Excess phosgene is then removed with nitrogen and thesolution is evaporated in vacuo. The residue is crystallized from ethylacetate whereupon pure N-(p-tolylsulphonyl)-tetrahydro-3H-3-benzazepine-Ii-carboximidoyl chloride is obtained.

What is claimed is:

l. A therapeutic composition consisting essentially of l. ahypoglycaemically effective amount of a compound of the formula SOZ N(y-N i ii R1 ll 0 wherein wherein R has the meaning as given in claim 1for R 3. A therapeutic composition as defined in claim 2 in which saidcompound is N-phenylsulfonyll ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 4. A therapeutic composition as defined inclaim 2 in which said compound is N-(p-tolylsulfonyl l,2,4,5-tetrahydro-3H-3- benzazepine-S-carboxamide. 5. A therapeuticcomposition as defined in claim 2 in which said compound is N-(p-chloro-phenylsulfonyl l ,2,4,5-tetrahydro-3I-l-3-benzazepine-3-carboxamide. 6. A therapeutic composition as defined inclaim 2 in which said compound is N-( p-fluoro-phenylsulfonyl)- l,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxamide. 7. A therapeuticcomposition as defined in claim 2 in which said compound is N-(p-methoxy-phenylsulfonyl l ,2,4,5-tetrahydro-3H-3-benzazepine-3carboxamide. 8. A therapeutic composition as definedin claim 2 in which said compound is N-( p-ethoxy-phenylsulfonyl l,2,4,5-tetrahydro-3 H- 3-benzazepine-S-carboxamide.

9. A therapeutic composition as defined in claim 2 in which saidcompound is N-( p-amino-phenylsulfonyl l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 10. A therapeutic composition as defined inclaim 2 in which said compound is N-(p-acetyl-phenylsulfonyl)- l,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxamide. 11. A therapeuticcomposition as defined in claim 2 in which said compound is N-(p-methylthio-phenylsulfonyl )-l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 12. A therapeutic composition as definedin claim I in which said compound is N-(o-tolylsulfonyl l,2,4,5-tetrahydro-3H-3- benzazepine-B-carboxamide. 13. A therapeuticcomposition as defined in claim 1 in which said compound is N-(m-chloro-phenylsulfonyl l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 14. A therapeutic composition as definedin claim 1 in which said compound is N-(indan-S-yl-sulfonyl l,2,4,5-tetrahydro-3H-3- benzazepine-3-carboxamide.

15. A process of producing a hypoglycaemic effect in a mammal whichcomprises administering to said mammal a hypoglycaemically efl'ectiveamount of a compound of the formula S O:NC[ m I I wherein R representshydrogen, halogen up to the atomic number 35, lower alkyl, lower alkoxy,lower alkylthio, lower alkanoyl or amino, R represents hydrogen or R Rrepresent trimethylene or tetramethylene, or a pharmaceuticallyacceptable addition salt thereof with inorganic or organic base. 16. Aprocess as defined in claim 15 in which said compound is of the formulawherein R has the meaning as given in claim 15 for R,.

17. A process as defined in claim 16 in which said compound isN-phenylsulfonyl-l ,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxamide.

18. A process as defined in claim 16 in which said compound isN-(p-tolysulfonyl l ,2,4,5-tetrahydro-3H-3- benzazepine-IS-carboxamide.19. A process as defined in claim 16 in which said compound isN-(p-chloro-phenylsulfonyl)- 1 ,2,4,5 -tetrahydro-3l-l-3-benzazepine-3-carboxamide. 20. A process as defined in claim 16 inwhich said compound is N-(p-fluoro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxamide. 21. A process asdefined in claim 16 in which said compound isN-(p-methoxy-phenylsulfonyl l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.

22. A process as defined in claim 16 in which said compound is N-(p-ethoxy-phenylsulfonyl l ,2 ,4,S-tetrahydro-3H-S-benzazepine-S-carboxamide.

23. A process as defined in claim 16 in which said 5 compound isN-(p-amin o-phenylsulfonyl)-l ,2,4,5-tetrahydro-3H-3-benzazepine-3-carb0xamide. 24. A process as defined in claim 16 inwhich said compound is N-( p-acetyl-phenylsulfonyl l,2,4,5-tetra.hydro-3H- 3-benzazepine-3-carboxamide. 25. A process asdefined in claim 16 in which said compound isN-(p-methylthio-phenylsulfonyl )-1 ,2,4,5 -tetrahydro- UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent 3,689 ,649 DatedSeptember 5 197,2

HENRI DIETRICH Inventofls) 7 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

On the cover sheet, insert [73] Assignee:

CIBA-GEIGY Corporation, Ardsley, New York, a corporation of New YorkColumn 13, lines 23 and 39, amend the right side of the structuralformula to read:

Signed and sealed this 6th day of August 1974.

(SEAL) Attest:

MCCOY M. GIBSON, JR.

c. MARSHALL DANN Attestlng Officer Commissioner of Patents

2. a pharmaceutical carrier.
 2. A therapeutic composition as defined inclaim 1 in which said compound is of the formula wherein R has themeaning as given in claim 1 for R1.
 3. A therapeutic composition asdefined in claim 2 in which said compound isN-phenylsulfonyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 4. Atherapeutic composition as defined in claim 2 in which said compound isN-(p-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.5. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-chloro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzaZepine-3-carboxamide.6. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-fluoro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.7. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-methoxy-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.8. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-ethoxy-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.9. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-amino-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.10. A therapeutic composition as defined in claim 2 in which saidcompound isN-(p-acetyl-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 11. A therapeutic composition as defined in claim 2 inwhich said compound isN-(p-methylthio-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 12. A therapeutic composition as defined in claim 1 inwhich said compound isN-(o-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.13. A therapeutic composition as defined in claim 1 in which saidcompound isN-(m-chloro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 14. A therapeutic composition as defined in claim 1 inwhich said compound isN-(indan-5-yl-sulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.15. A process of producing a hypoglycaemic effect in a mammal whichcomprises administering to said mammal a hypoglycaemically effectiveamount of a compound of the formula wherein R1 represents hydrogen,halogen up to the atomic number 35, lower alkyl, lower alkoxy, loweralkylthio, lower alkanoyl or amino, R2 represents hydrogen or R1R2represent trimethylene or tetramethylene, or a pharmaceuticallyacceptable addition salt thereof with inorganic or organic base.
 16. Aprocess as defined in claim 15 in which said compound is of the formulawherein R has the meaning as given in claim 15 for R1.
 17. A process asdefined in claim 16 in which said compound isN-phenylsulfonyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 18.A process as defined in claim 16 in which said compound isN-(p-tolysulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.19. A process as defined in claim 16 in which said compound isN-(p-chloro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 20. A process as defined in claim 16 in which saidcompound isN-(p-fluoro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 21. A process as defined in claim 16 in which saidcompound isN-(p-methoxy-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 22. A process as defined in claim 16 in which saidcompound isN-(p-ethoxy-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 23. A process as defined in claim 16 in which saidcompound is N-(p-amino-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide. 24.A process as defined in claim 16 in which said compound isN-(p-acetyl-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 25. A process as defined in claim 16 in which saidcompound isN-(p-methylthio-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 26. A process as defined in claim 15 in which saidcompound isN-(o-tolylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.27. A process as defined in claim 15 in which said compound isN-(m-chloro-phenylsulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.
 28. A process as defined in claim 15 in which saidcompound isN-(indan-5-yl-sulfonyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxamide.